The present invention relates to the field of pharmacology and, more particularly, to heterocyclic compounds and their use in the treatment of medical conditions associated with the serotonergic system and/or dopaminergic system, including, for example, sexual disorders and various CNS diseases and disorders.
Erectile dysfunction (ED), the most common sexual arousal disorder, involves partial or complete failure to attain or maintain a penile erection adequately for intercourse. Erectile dysfunction is a very common problem, affecting from about 40 to 60 percents of men at some time in their life, and about 52 percents of men between 40 and 70 years old.
Penile erection occurs when blood vessels in the penis, particularly in the corpus cavernosum, become filled with large volumes of blood, causing an enlargement and stiffening of the organ. In response to stimuli from the cerebral cortex and/or the parasympathetic nervous system, nitric oxide is released in penile arteries. Nitric oxide causes the smooth muscle in arteries to relax by activating guanylyl cyclase, increasing the concentration of cyclic guanosine monophosphate (cGMP), which activates protein kinase G. The relaxation of the arterial smooth muscle causes the arteries to expand, increasing the volume of blood flowing through the arteries. The increased volume of blood entering the penis leads to an erection. In women, clitoral erection is caused by an analogous mechanism.
The biological effect of nitric oxide is limited by phosphodiesterases (PDEs) which hydrolyze cGMP Inhibition of PDEs increases the levels of cGMP induced by nitric oxide, thereby magnifying the effects of nitric oxide.
PDE5, first purified and characterized from rat (Francis and Corbin, 1988), is very abundant in vascular smooth muscle cells and appears to play a significant role in modulating smooth muscle tone in general and penile corpus cavernosal smooth muscle tone in particular (Beavo, 1998; Moreland and Goldstein, 1995). Selective inhibitors of PDE5 have therefore been suggested for inducing penile (and clitoral) erection by raising cGMP levels (Tenet et al., 1996).
The principal currently available drugs belonging to the PDE5 inhibitors family are tadalafil (Cialis™), vardenafil (Levitra™) and sildenafil (Viagra™), the most famous one being Viagra™ (sildenafil).
Although sildenafil is considered a selective inhibitor of PDE5, it has long been recognized that it effects on other body organs and hence its use is associated with several adverse side effects such as nausea, headache, and cutaneous flushing. These clinically significant adverse effects are thought to be due to nonspecific inhibition of other PDEs exhibited by this compound (Beavo, 1998; Moreland and Goldstein, 1995).
In addition to PDE5, experimental data indicate that several neurotransmitters and neuropeptides in the central nervous system are involved in the control of penile erection and sexual behavior, one such prominent neurotransmitter being dopamine (Melis and Argiolas, 1995; Andersson, 2001). In contrast to PDE5 inhibition, which directly affects the blood vessels in the penis, dopamine is involved in the regulation of penile activity by the central nervous system.
Dopamine is one of the key mediators in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward and hormonal regulation. Dopamine receptors in mammalian tissues have been classified as D1-like (D1 and D5) and D2-like (D2, D3, and D4) (Missale, 1998). It has been shown that several dopamine receptor agonists such as apomorphine, quinpirole, quinelorane, and (−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) induce penile erection after systemic administration in mammals (Melis and Argiolas, 1995).
Recent demonstration that apomorphine can facilitate penile erection in erectile dysfunction patients has introduced a new approach to pharmacological correction of erectile dysfunction. It is believed that apomorphine induces penile erection by activating the D4 receptor, although other dopamine receptors may also be involved (Brioni et al., 2004). However, apomorphine is classified as a nonselective agonist because it activates all of the dopamine receptor subtypes (Missale, 1998). It is believed that such non-selectivity is associated with the known emetic action that substantially restricts the practical application of apomorphine. It has therefore been considered desirable to obtain selective D4 agonists.
One selective D4 agonist that was found active in penile erection is ABT-724 (2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole) (Brioni et al., 2004). Methods of using ABT-724 and related compounds in the treatment of various sexual dysfunctions are disclosed in U.S. Pat. Nos. 7,022,728 and 6,960,589, to Cowart et al. The chemical structures of apomorphine and ABT-724 are presented in Scheme 1 below.

Other highly selective dopamine receptor D4 agonists have also been developed. These include, for example, PD-168077 and PIP3EA (Melis et al., 2006), A-412997 (Moreland et al., 2005) and A-381393 (Nakane et al., 2005). These compounds are structurally similar to ABT-724, comprising substituted phenyl groups instead of the pyridine group in ABT-724. In addition, PIP3EA comprises 2-imidazo[1,2-a]pyridine instead of the benzoimidazole in ABT-724, A-412997 and PD-168077 comprise a monocyclic aryl group linked by an amide bond instead of benzoimidazole, and A-412997 comprises piperidine instead of piperazine.
In view of the significance of certain types of dopamine receptors in the control of sexual behavior and penile erection, the discovery of ABT-724 (Brioni et al, 2004; Cowart et al, 2004) and development of other highly selective dopamine receptor D4 agonists (Moreland, 2001) have provided a new strategy for the treatment of erectile dysfunction. A further potential advantage for the use of dopamine receptor agonists is the ability of dopamine receptor agonists, selective D4 agonists in particular, to treat a range of sexual disorders.
An example of another type of sexual disorder is the orgasm disorder, in which orgasm and/or ejaculation are absent or delayed to a degree in which sexual satisfaction is significantly reduced, even in the presence of an adequate erection. One common cause of orgasm disorder is selective serotonin reuptake inhibitor (SSRI) therapy.
Dopamine has been found to regulate ejaculation via D2-like receptors (Wolters & Hellstrom, 2006). Bupropion and amantadine, which stimulate dopamine pathways, have been reported to reverse orgasm disorders (Modell et al., 2000; Balon, 1996), and SSRI-induced orgasm disorders are suspected to be induced by inhibition of dopamine pathways (Alcantara, 1999). PDE5 inhibitors have also been found to reverse SSRI-induced orgasm disorders (Ashton, 2004; Damis et al., 1999).
Another example of a type of sexual disorder is decreased libido, or sexual desire disorder, which is often attributed to aging, psychological disorders such as depression, and medications such as SSRIs.
Dopamine release plays an important role in sexual desire, apparently as part of the general role of dopamine in providing motivation for rewarding activities (Giuliano and Allard, 2001). Consequently, dopamine antagonists tend to reduce sexual desire (Stimmel and Gutierrez, 2006). The D4 receptor in particular has been linked to sexual desire, as well as sexual arousal and function (Ben-Zion et al., 2006).
Another key mediator of the CNS is 5-hydroxytryptamine (5-HT), also known as serotonin. 5-HT is involved in the regulation of anger, aggression, body temperature, moods, sleep, vomiting and appetite, as well as sexuality. Several families of 5-HT receptors are known.
U.S. Pat. No. 3,976,776 discloses compounds comprised of heteroaryl-piperazinylalkyl derivatives of azaspiroalkanediones having tranquilizing and anti-emetic properties. U.S. Pat. No. 4,182,763 discloses a method of treating anxiety by administering buspirone, a heteroaryl-piperazinylalkyl derivative of an azaspiroalkanedione, as a 5-HT1A receptor agonist. Buspirone is commonly used for this purpose. U.S. Pat. No. 5,162,321 discloses 1-naphthyl-piperazinyl alkyl derivatives, including derivatives of azaspiroalkanediones, for use as 5-HT1A receptor ligands, and methods of using such ligands to treat migraine, depression, anxiety, schizophrenia, stress, pain and hypertension.
Buspirone has also been disclosed by U.S. Pat. No. 4,640,921 to effectively treat sexual dysfunction in both male and female subjects. However, buspirone causes numerous side effects, most frequently vertigo, headaches, nervousness, agitation, light-headedness and nausea. In addition, the effect of buspirone is drastically increased by grapefruit consumption, leading to the danger of overdosing.
The chemical structure of buspirone is presented in Scheme 2 below:

As the 5-HT1A receptor is localized to the CNS, it is believed that 5-HT1A receptor activation alleviates sexual dysfunction by regulating the CNS, similar to the mechanism of dopamine receptor activation.
WO/2005/007166, which is incorporated by reference as if fully set forth herein, teaches the use of PDE-5 inhibitors, in combination with 5HT1A agonists for the treatment of sexual dysfunction, particularly female sexual arousal disorder (FSAD) with concomitant hypoactive sexual desire disorder (HSDD).
Additional indications which have been associated with modulation, activation in particular, of the 5-HT1A receptor include, for example, disorders of the outer retina (see, WO 2001/070222); CNS disorders such as depression, anxiety, neurodegenerative diseases, panic, alcohol and drug addiction, sleep disorders, cognitive disorders, Alzheimer's disease, Parkinson's disease and schizophrenia (see, for example, WO 2004/041815, WO 2003/078420 and WO 2000/035878); and neuronal stem cell differentiation (see, for example, WO 2002/102988). All of the aforementioned publications are incorporated by reference as if fully set forth herein.
Thus, the art teaches agents that act via the dopamine pathway, as well as agents that act via the 5-HT pathway, for treating medical conditions such as sexual disorders and related disorders, as well as CNS disorders such as anxiety and related mood disorder. The clinical effect of most of these agents, however, has not been practiced yet, and, moreover, the utilization of most of these agents is associated with adverse side effects, mostly stemming from the non-selectively thereof.